In the United States, the use of tobacco products is responsible for over 450,000 premature deaths per year (about 20% of all premature deaths) and accounts for around $100 billion dollars per year in health care costs. Despite these facts, approximately 25% of adults in the United States continue to smoke. Typically, however, even heavy smokers can abstain from smoking during the normal sleep cycle and wake no more frequently during the night than do non-smokers. This observation suggests that there may be circadian patterns in which craving for nicotine is reduced at night. In support of this possibility, recent studies have demonstrated that sensitivity to drugs of abuse is generally reduced at night as well as altered by mutations in genes that regulate the circadian clock. In addition, melatonin, a hormone whose synthesis peaks at night, decreases craving in abstinent smokers and reduces sensitivity to the rewarding properties of some drugs of abuse in rodents. Despite this information, very little research has been done to assess circadian variations in sensitivity to nicotine. In the experiments outlined in this proposal, we will perform exploratory studies in mice in order to define the circadian pattern of sensitivity to the acute effects of nicotine. We also will examine whether any identified variation in sensitivity to nicotine is associated with circadian variations in melatonin synthesis, nicotinic receptor expression and/or nicotine metabolism. Finally, we will determine whether melatonin signaling through melatonin receptors is required for circadian variations in nicotine sensitivity, nicotinic receptor expression and nicotine metabolism. These studies will identify time points, mouse strains and potential mechanisms that will guide future studies to understand the mechanisms that regulate altered sensitivity to nicotine over the course of the circadian cycle. Such knowledge may provide novel insights into the neurobiology of nicotine addiction. to public health: Understanding the role of daily variations in nicotine sensitivity and the potential role of melatonin on regulating these daily variations in nicotine sensitivity may provide insight into why smokers typically can sleep through the night without the need for a cigarette. This knowledge would be extremely useful for the development of better methods to treat nicotine addiction. [unreadable] [unreadable] [unreadable]